Pharmacokinetics Of Metoprolol Research Articles

Simultaneous determination of metoprolol and its metabolites, α‐hydroxymetoprolol and O‐desmethylmetoprolol, in human plasma by liquid chromatography with tandem mass spectrometry: Application to the pharmacokinetics of metoprolol associated with CYP2D6 genotypes

A rapid and simple LC with MS/MS method for the simultaneous determination of metoprolol and its two CYP2D6-derived metabolites, α-hydroxy- and O-desmethylmetoprolol, in human plasma was established. Metoprolol (MET), its two metabolites, and the internal standard chlorpropamide were extracted from plasma (50 μL) using ethyl acetate. Chromatographic separation was performed on a Luna CN column with an isocratic mobile phase consisting of distilled water and methanol containing 0.1% formic acid (60:40, v/v) at a flow rate of 0.3 mL/min. The total run time was 3.0 min per sample. Mass spectrometric detection was conducted by ESI in positive ion selected-reaction monitoring mode. The linear ranges of concentration for MET, α-hydroxymetoprolol, and O-desmethylmetoprolol were 2-1000, 2-500, and 2-500 ng/mL, respectively, with a lower limit of quantification of 2 ng/mL for all analytes. The coefficient of variation for the assay's precision was ≤ 13.2%, and the accuracy was 89.1-110%. All analytes were stable under various storage and handling conditions and no relevant cross-talk and matrix effect were observed. Finally, this method was successfully applied to assess the influence of CYP2D6 genotypes on the pharmacokinetics of MET after oral administration of 100mg to healthy Korean volunteers.

The effect of AST-120 on the single-dose pharmacokinetics of metoprolol extended-release tablets in healthy subjects

This was a randomized, open-label, three-way crossover study to assess the effects of AST-120 (an orally administered spherical carbon adsorbent acting in the gastrointestinal tract without systemic circulation) on the single-dose pharmacokinetics of metoprolol in an extended-release formulation (metoprolol ER) in healthy volunteers. A total of 34 subjects were singly administered metoprolol ER alone (A), and metoprolol ER in combination with AST-120 simultaneously (B) and 1 h later (C). The total exposure was more significantly reduced in both treatments B and C than that in treatment A; the geometric mean ratios of area under the curve extrapolated to infinity (AUC0-∞) for B/A and C/A were reduced by approximately 30% in both treatments B and C. Maximum observed plasma concentration (Cmax) of metoprolol in treatment B significantly decreased, whereas Cmax in treatment C was slightly decreased. AST-120 treatment was unlikely to affect apparent first-order terminal elimination half-life (T1/2) of metoprolol significantly. Reduction in heart rate and blood pressure readings were similar across the treatment periods. Coadministration of AST-120 and metoprolol ER was safe and was well tolerated. Because AST-120 reduced gastrointestinal absorption of metoprolol ER, careful monitoring of heart rate and blood pressure is recommended in coadministration of AST-120 with metoprolol ER.

The effect of mirabegron, a potent and selective β3-adrenoceptor agonist, on the pharmacokinetics of CYP2D6 substrates desipramine and metoprolol

Mirabegron is a potent and selective β3-adrenoceptor agonist developed for the treatment of overactive bladder. In vitro studies demonstrated that mirabegron partly acts as a (quasi-) irreversible, metabolism-dependent inhibitor of CYP2D6. The effect of steady-state mirabegron on single doses of the sensitive CYP2D6 substrates metoprolol (100mg) and desipramine (50mg) was assessed in two open-label, one-sequence crossover studies in healthy subjects (CYP2D6 extensive metabolizers). Mirabegron 160mg/day increased metoprolol maximum plasma concentration (C max) 1.90-fold (90% confidence interval [CI] 1.54; 2.33) and total exposure (AUC0-∞) 3.29-fold (90% CI 2.70; 4.00) in 12 males (study 1). Mean metoprolol half-life increased from 2.96 to 4.11h. α-Hydroxymetoprolol C max and AUC to last measurable concentration decreased 2.6-fold and 2.2-fold, respectively. In study 2, mirabegron 100mg/day increased desipramine C max 1.79-fold (90% CI 1.69; 1.90) and AUC0-∞ 3.41-fold (90% CI 3.07; 3.80) in 14 males and 14 females. Mean desipramine half-life increased from 19.5 to 35.8h. C max of 2-hydroxydesipramine decreased ~twofold, while AUC increased ~1.3-fold. Desipramine was administered again 2weeks after the last mirabegron dose. Desipramine C max and AUC0-∞ were still ~1.13-fold increased; the 90% CIs fell within the 0.80-1.25 interval. All treatments were well tolerated. In conclusion, mirabegron is a moderate CYP2D6 inhibitor (ratio and 90% CI <5.0).

A Meta-Analysis of CYP2D6 Metabolizer Phenotype and Metoprolol Pharmacokinetics

Metoprolol, a commonly prescribed beta-blocker, is primarily metabolized by cytochrome P450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Several smaller studies have shown that metoprolol pharmacokinetics is influenced by CYP2D6 genotype and metabolizer phenotype. To increase robustness of metoprolol pharmacokinetic estimates, a systematic review and meta-analysis of pharmacokinetic studies that administered a single oral dose of immediate release metoprolol was performed. Pooled analysis (n= 264) demonstrated differences in peak plasma metoprolol concentration, area under the concentration-time curve, elimination half-life, and apparent oral clearance that were 2.3-, 4.9-, 2.3-, and 5.9-fold between extensive and poor metabolizers, respectively, and 5.3-, 13-, 2.6-, and 15-fold between ultra-rapid and poor metabolizers (all p<0.001). Enantiomer-specific analysis revealed genotype-dependent enantio-selective metabolism, with nearly 40% greater R- vs S-metoprolol metabolism in ultra-rapid and extensive metabolizers. This study demonstrates a marked effect of CYP2D6 metabolizer phenotype on metoprolol pharmacokinetics and confirms enantiomer specific metabolism of metoprolol.

Influence of Duloxetine on the in-vivo pharmacokinetics of Metoprolol in rat model

BackgroundIt is widely accepted that Duloxetine and Metoprolol are concomitantly administered for clinical conditions like diabetic neuropathic pain and diabetic cardiovascular disorders respectively. Since these two drugs interfere with Cytochrome P2D6 (CYP2D6), there is likelihood of possible potential drug–drug interactions between these two drugs. Hence, this study was undertaken to investigate the effect of Duloxetine on the in-vivo pharmacokinetics of Metoprolol in rat models. MethodsIn-vivo pharmacokinetic studies were performed on rats. Rats were treated with Duloxetine (20 mg/kg) and Metoprolol (25 mg/kg) orally and blood samples were collected (0), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12 and 24 h post treatment. Plasma concentration of Metoprolol was estimated by Reverse Phase High Performance Liquid Chromatography (RP-HPLC) method. ResultsDuloxetine treatment along with Metoprolol results in 3.38 fold significant (p < 0.01) increase in the area under the curve (AUC0–24) of Metoprolol, three fold significant (p < 0.01) increase in the AUC0–α of Metoprolol, 3.4 fold increase in T1/2 of Metoprolol without significant alteration in maximum concentration (Cmax) of Metoprolol. ConclusionsConcomitant administration of Duloxetine and Metoprolol orally in rat models results in increased exposure (AUC) of Metoprolol without significant increase in maximum concentration. This interaction could be of clinical significance if it is confirmed in human studies.

A Physiologically Based Pharmacokinetic Model to Predict Disposition of CYP2D6 and CYP1A2 Metabolized Drugs in Pregnant Women

Conducting pharmacokinetic (PK) studies in pregnant women is challenging. Therefore, we asked if a physiologically based pharmacokinetic (PBPK) model could be used to evaluate different dosing regimens for pregnant women. We refined and verified our previously published pregnancy PBPK model by incorporating cytochrome P450 CYP1A2 suppression (based on caffeine PK) and CYP2D6 induction (based on metoprolol PK) into the model. This model accounts for gestational age-dependent changes in maternal physiology and hepatic CYP3A activity. For verification, the disposition of CYP1A2-metabolized drug theophylline (THEO) and CYP2D6-metabolized drugs paroxetine (PAR), dextromethorphan (DEX), and clonidine (CLO) during pregnancy was predicted. Our PBPK model successfully predicted THEO disposition during the third trimester (T3). Predicted mean postpartum to third trimester (PP:T3) ratios of THEO area under the curve (AUC), maximum plasma concentration, and minimum plasma concentration were 0.76, 0.95, and 0.66 versus observed values 0.75, 0.89, and 0.72, respectively. The predicted mean PAR steady-state plasma concentration (Css) ratio (PP:T3) was 7.1 versus the observed value 3.7. Predicted mean DEX urinary ratio (UR) (PP:T3) was 2.9 versus the observed value 1.9. Predicted mean CLO AUC ratio (PP:T3) was 2.2 versus the observed value 1.7. Sensitivity analysis suggested that a 100% induction of CYP2D6 during T3 was required to recover the observed PP:T3 ratios of PAR Css, DEX UR, and CLO AUC. Based on these data, it is prudent to conclude that the magnitude of hepatic CYP2D6 induction during T3 ranges from 100 to 200%. Our PBPK model can predict the disposition of CYP1A2, 2D6, and 3A drugs during pregnancy.

Cytochrome P450 2D6 phenotype and genotype in hypertensive patients on long-term therapy with metoprolol

The aim was to compare cytochrome P450 2D6 phenotype and genotype using metoprolol as a probe drug. Further, to investigate the influence of P450 2D6 activity on metoprolol pharmacokinetics and pharmacodynamics in patients on metoprolol therapy. Cytochrome P450 2D6 is a highly polymorphic enzyme that contributes to the variability of metoprolol. However, environmental factors also modify drug disposition. Forty-nine hypertensive patients were enrolled. Serum metoprolol and α-hydroxymetoprolol concentrations, resting heart rate were measured before, 1, 3 and 4 hours post-dose. Significantly higher normalized metoprolol serum concentrations, normalized metoprolol AUC0-4 and metoprolol oral clearance were observed in patients with lower P450 2D6 metabolic activity. A trend towards a lower resting heart rate before metoprolol intake was also observed in this group of patients. The differences in metoprolol disposition were more expressed when P450 2D6 phenotype instead of genotype was determined. Significant variations exist in metoprolol disposition in hypertensive patients. Both genotyping and phenotyping provides a valuable method in determining the enzymatic activity and in optimising metoprolol therapy (Tab. 3, Fig. 8, Ref. 35).

Pharmacokinetics and first-pass elimination of metoprolol in rats: contribution of intestinal first-pass extraction to low bioavailability of metoprolol

The pharmacokinetics of metoprolol after intravenous (IV) (0.5, 1, and 2 mg/kg) and oral (1, 2, and 5 mg/kg) administration, and the intestinal and hepatic first-pass extraction of metoprolol after IV, intraportal, and intraduodenal (1 and 2 mg/kg) administration were comprehensively assessed in rats.Metoprolol exhibited dose-independent pharmacokinetics after IV administration, and dose-dependent pharmacokinetics after oral administration probably due to the saturable first-pass extraction of metoprolol. At doses where metoprolol exhibited dose-independent pharmacokinetics (1 and 2 mg/kg), complete absorption (>99.2%) and low F (<0.245) after oral administration were observed. The intestinal and hepatic first-pass extraction ratio (EG and EH, respectively) of metoprolol were approximately 0.45 and 0.60, respectively (equivalent to approximately 45% and 30% of orally administered dose, respectively), suggesting considerable contribution of intestinal first-pass extraction to the low F of metoprolol in rats.The EG in rats was predicted from in vitro clearance and/or permeability data utilizing the QGut model and well-stirred model (0.347 and 0.626, respectively). The predicted EG values were in good agreement with the observed in vivo EG (0.492–0.443), suggesting the utility of the prediction of in vivo intestinal first-pass extraction from the in vitro clearance using intestinal microsomes.

Effects of Flos carthami on CYP2D6 and on the Pharmacokinetics of Metoprolol in Rats

Flos carthami is a traditional Chinese herbal medicine. Clinically, the Flos carthami Injection has been used concomitantly with other Western drugs and may be used concomitantly with β-blockers, such as metoprolol, to treat cerebrovascular and coronary heart diseases, in China. Metoprolol is a CYP2D6 substrate and is predominantly metabolized by this isozyme. However, we do not know whether there is an effect of Flos carthami on CYP2D6 and the consequences of such an effect. Concern is raised regarding the possible herb-drug interaction. In this report, the effects of Flos carthami on the activity of CYP2D6 in vivo and in vitro and on the pharmacokinetics of metoprolol, in rats, are investigated. To assess the inhibitory potency of Flos carthami, the concentration associated with 50% inhibition (IC50) of dextromethorphan metabolism was determined based on the concentration-inhibition curves. The inhibitory effect of Flos carthami on CYP2D6 was also compared with cimetidine in vitro. Flos carthami could significantly inhibit CYP2D6 in rats both in vitro and in vivo (P < .05) and could slow down the metabolic rate of metoprolol as suggested by prolonged t1/2 (67.45%), by increased C max (74.51%) and AUC0−∞ (76.89%). These results suggest that CYP2D6 is a risk factor when Flos carthami is administered concomitantly with metoprolol or other CYP2D6 substrates.

The effects of salvianolic acid B from radix salvia miltiorrhizae on the oral pharmacokinetics of metoprolol and metoprolol acid in rats

The present study aimed to investigate the effects of salvianolic acid B (SalB) isolated from Radix Salvia miltiorrhizae on the oral pharmacokinetics of metoprolol (MET) and metoprolol acid (META) in rats. The pharmacokinetic parameters of MET and META were measured after oral (15 mg/kg) administration of MET in rats in the presence and absence of SalB. Compared to the control given MET alone, with the concurrent administration of SalB (50 mg/kg), the AUC and C(max) of MET increased by 51.7% and 27.7%, and the AUC and C(max) of META decreased by 26.5% and 19.6%, respectively. With the presence of SalB, the metabolic ratio was markedly decreased by 50.8%. However, no significant changes were observed in the pharmacokinetic parameters of SalB when it was combined with MET.

心不全の個別薬物療法を目的としたβ遮断薬の体内動態変動機構と人種差に関する研究

We previously reported that the pharmacokinetics of metoprolol varied greatly among 34 Japanese patients in which the drug was routinely administered due to genetic polymorphisms of CYP2D6 (CYP2D6 *10 ),and that the racial differences in allele frequencies may be responsible for differences in metoprolol therapeutic dose ranges between Caucasians and Japanese.The aim of the present study was to evaluate mechanisms for pharmacokinetic variability of carvedilol and bisoprolol for personalization of β-blocker therapy in Japanese patients with heart failure (HF).The CL /F value of S-carvedilol was decreased in healthy Japanese subjects with CYP2D6 *10 ,although the effect of CYP2D6 *10 was not significant in HF patients.In addition,it was suggested that the activity for CYP2D6 and other carvedilol-metabolizing enzymes was decreased in HF patients.On the other hand,the CL /F value of bisoprolol was decreased in elderly patients.However,pharmacokinetic variability of bisoprolol was small even in routinely treated patients,provided that both body weight and renal function were taken into account for the prediction of CL /F of the drug.These results suggest that bisoprolol is a useful βblocker for the treatment of HF patients.

Influence ofCYP2D6*10on the pharmacokinetics of metoprolol in healthy Korean volunteers

Genetic polymorphism of CYP2D6 leads to differences in pharmacokinetics of CYP2D6 substrates. The CYP2D6*10 allele is clinically important in Koreans because of its high frequency in Asians. We investigated whether the pharmacokinetics of metoprolol was altered by the presence of the CYP2D6*10 allele in Korean subjects. One hundred and seven volunteers were recruited and grouped as CYP2D6*1/*1, CYP2D6*1/*10 and CYP2D6*10/*10 according to their genotypes. Metoprolol tartrate 100 mg (Betaloc) was administered orally once to each subject in these three groups (n = 6, 7 and 5, respectively). The pharmacokinetic parameters of metoprolol and its metabolite, alpha-hydroxymetoprolol, and the metabolic ratio for the three groups were estimated and compared. The area under the plasma concentration-time curve (AUC(0-->infinity)), the maximum plasma concentration (C(max)) and the elimination half-life (T(1/2)) of metoprolol and alpha-hydroxymetoprolol for the CYP2D6*10/*10 group were all significantly different from those of the CYP2D6*1/*1 group (P < 0.05). The AUC(0-->infinity)s of metoprolol were 443.7 +/- 168.1, 995.6 +/- 321.4 and 2545.3 +/- 632.0 ng.h/mL, and the AUC(0-->infinity)s of alpha-hydroxymetoprolol were 1232.0 +/- 311.2, 1344.0 +/- 288.1 and 877.4 +/- 103.4 ng.h/mL for groups CYP2D6*1/*1, *1/*10 and *10/*10, respectively. The corresponding T(1/2) values of metoprolol were 2.7 +/- 0.5, 3.2 +/- 1.3 and 5.0 +/- 1.1 h, while those of alpha-hydroxymetoprolol were 5.4+/-1.5, 6.0 +/- 1.4 and 10.5 +/- 4.2 h, respectively. The metabolic ratios of the three groups were significantly different (P < 0.05). The CYP2D6*10 allele altered the pharmacokinetics of metoprolol in Korean subjects and is likely to affect other drugs metabolized by the CYP2D6 enzyme, similarly.

Enantiospecific pharmacokinetics of metoprolol in CYP2D6 ultra-rapid metabolizers and correlation with exercise-induced heart rate

Our objective was to study the enantioselective pharmacokinetics of metoprolol in CYP2D6 ultra-rapid metabolizers (UM) compared with extensive (EM) and poor (PM) metabolizers to quantify differential effects of metoprolol enantiomers on the beta1-adrenoreceptor blockade. Twenty-nine healthy individuals were selected based on their CYP2D6 genotype, and 100 mg racemic metoprolol was administered. Plasma concentrations of R- and S-metoprolol and the metabolites SS-, SR-, RS-, and RR-hydroxymetoprolol were quantified by high-performance liquid chromatography. Mean (+/-SD) AUCs of S-metoprolol were 190 +/- 99 ng/ml x h in UMs, 366 +/- 158 in EMs, and 1,804 +/- 300 in PMs. For R-metoprolol, the AUCs were 127 +/- 72 ng/ml x h in UMs, 261 +/- 126 in EMs, and 1,746 +/- 319 in PMs. The concentrations of R-metoprolol and S-metoprolol, respectively, needed to obtain a half-maximum reduction in heart rate were estimated as 20 and 21 ng/ml in PMs, 11 and 17 ng/ml in EMs, and 7 and 11 ng/ml in UMs. A slight enantiopreference towards metabolism of R-metoprolol by CYP2D6 was observed in EMs and even more in the UM group, but the effect was far from being enantioselective.

Effects of imatinib (Glivec) on the pharmacokinetics of metoprolol, a CYP2D6 substrate, in Chinese patients with chronic myelogenous leukaemia

Imatinib, a tyrosine kinase inhibitor, exhibits a competitive inhibition on the CYP450 2D6 isozyme with a K(i) value of 7.5 microm. However, the clinical significance of the inhibition and its relevance to 2D6 polymorphisms have not been evaluated. The pharmacokinetics of imatinib have been well studied in Caucasians, but not in a Chinese population. Metoprolol, a CYP2D6 substrate, has different clearances among patients with different CYP2D6 genotypes. It is often used as a CYP2D6 probe substrate for clinical drug-drug interaction studies. Co-administration of imatinib at 400 mg twice daily increased the plasma AUC of metoprolol by approximately 23% in 20 Chinese patients with chronic myeloid leukaemia (CML), about 17% increase in CYP2D6 intermediate metabolizers (IMs) (n = 6), 24% in extensive metabolizers (EMs) (n = 13), and 28% for the subject with unknown 2D6 status (n = 1) suggesting that imatinib has a weak to moderate inhibition on CYP2D6 in vivo. * The clearance of imatinib in Chinese patients with CML showed no difference between CYP2D6 IMs and EMs, and no major difference from Caucasian patients with CML based on data reported in the literature. AIMS To investigate the effect of imatinib on the pharmacokinetics of a CYP2D6 substrate, metoprolol, in patients with chronic myeloid leukaemia (CML). The pharmacokinetics of imatinib were also studied in these patients. Patients (n = 20) received a single oral dose of metoprolol 100 mg on day 1 after an overnight fast. On days 2-10, imatinib 400 mg was administered twice daily. On day 8, another 100 mg dose of metoprolol was administered 1 h after the morning dose of imatinib 400 mg. Blood samples for metoprolol and alpha-hydroxymetoprolol measurement were taken on study days 1 and 8, and on day 8 for imatinib. Of the 20 patients enrolled, six patients (30%) were CYP2D6 intermediate metabolizers (IMs), 13 (65%) extensive metabolizers (EMs), and the CYP2D6 status in one patient was unknown. In the presence of 400 mg twice daily imatinib, the mean metoprolol AUC was increased by 17% in IMs (from 1190 to 1390 ng ml(-1) h), and 24% in EMs (from 660 to 818 ng ml(-1) h). Patients classified as CYP2D6 IMs had an approximately 1.8-fold higher plasma metoprolol exposure than those classified as EMs. The oral clearance of imatinib was 11.0 +/- 2.0 l h(-1) and 11.8 +/- 4.1 l h(-1) for CYP2D6 IMs and EMs, respectively. Co-administration of a high dose of imatinib resulted in a small or moderate increase in metoprolol plasma exposure in all patients regardless of CYP2D6 status. The clearance of imatinib showed no difference between CYP2D6 IMs and EMs.

Comparison of Duloxetine, Escitalopram, and Sertraline Effects on Cytochrome P450 2D6 Function in Healthy Volunteers

This study is the first to directly compare the relative effects of duloxetine, escitalopram, and sertraline on the functional activity of the drug-metabolizing cytochrome P450 2D6 enzyme as assessed by changes in the pharmacokinetics of the cytochrome P450 2D6 model substrate drug, metoprolol. Single-dose pharmacokinetics of metoprolol were measured before and after 17 days of treatment with escitalopram 20 mg/d, duloxetine 60 mg/d, or sertraline 100 mg/d in young healthy male and female participants. The outcome measures were changes in metoprolol peak plasma levels, area under the plasma concentration-time curve, and clearance. The results were tested using paired t tests and independent t tests. The addition of each drug produced statistically significant changes in metoprolol pharmacokinetics. The rank order for the change in metoprolol area under the plasma concentration-time curve was duloxetine (180%) > escitalopram (89%) > sertraline (48% and 67%). Compared with sertraline, duloxetine produced statistically significantly larger changes in metoprolol pharmacokinetic parameters. The changes produced by escitalopram and sertraline were not statistically different.

Mixture Models and Subpopulation Classification: A Pharmacokinetic Simulation Study and Application to Metoprolol CYP2D6 Phenotype

Mixture models are applied in population pharmacometrics to characterize underlying population distributions that are not adequately approximated by a single normal or lognormal distribution. In addition to obtaining individualized maximum a posteriori Bayesian post hoc parameter estimates, the subpopulation to which an individual was classified can be determined. However, the accuracy of the classification of subjects to subpopulations is not well studied. We investigated the impact of several factors on the accuracy of classification in mixture models applied to pharmacokinetics using a simulation strategy. The availability of actual subject data allowed us to evaluate mixture model classification in a potentially common application, namely, the classification of clearance into poor metabolizer (PM) or extensive metabolizer (EM) subgroups with the known phenotype status in subjects receiving metoprolol. The factors explored in the simulation study were the magnitude of difference between the clearances in two subpopulations, the between subject variability in clearance, the mixing-fraction, and the population sample size. Populations were simulated at various levels of the above factors and analyzed with a mixture model using NONMEM. The population pharmacokinetics of metoprolol were modeled with the EM/PM phenotype as a known covariate, and without the phenotype covariate using a mixture model. Within the range of scenarios studied, the proportion of subjects classified into the correct subpopulation was high. The simulation-estimation study suggests that a greater separation between two subpopulations, a smaller variability in the parameter distribution, a larger sample size, and a smaller size subpopulation tend to be associated with a greater accuracy of subpopulation classification when a mixture model is applied to pharmacokinetic data. In a population pharmacokinetic analysis of metoprolol, a drug that undergoes polymorphic metabolism, it was possible to correctly identify phenotype status using a mixture model.

β-adrenergic Receptor Polymorphisms and Responses during Titration of Metoprolol Controlled Release/extended Release in Heart Failure*

beta-Blockers require careful initiation and titration when used in patients with heart failure. Some patients tolerate beta-blocker therapy initiation without difficulty, whereas in other patients this period presents clinical challenges. We tested the hypothesis that polymorphisms at codons 389 (Arg389Gly) and 49 (Ser49Gly) of the beta(1)-adrenergic receptor would be associated with differences in initial tolerability of beta-blocker therapy in patients with heart failure. We also tested whether polymorphisms in the beta(2)-adrenergic receptor, G-protein alpha s subunit (G(s)alpha), and cytochrome P450 (CYP) 2D6 genes or S-metoprolol plasma concentrations were associated with beta-blocker tolerability. Sixty-one beta-blocker-naive patients with systolic heart failure were prospectively enrolled. Patients began taking 12.5 to 25 mg metoprolol controlled release/extended release with titration every 2 weeks (as tolerated) to 200 mg/d or the maximum tolerated dose over a period of 8 to 10 weeks. Decompensation was the composite of death, heart failure hospitalization, increase in other heart failure medications, or need to discontinue metoprolol. End points were assessed during the titration period. The overall rate of decompensation was not different between the codon 49 or 389 genotypes. However, a significantly greater percentage of patients with the Gly389 variant required increases in heart failure medications as compared with Arg389 homozygotes (48% versus 14%, respectively; P = .006). Similarly, patients with the Ser49 homozygous genotype were significantly more likely to require increases in concomitant heart failure therapy as compared with Gly49 carriers (41% versus 11%, respectively; P = .03). Neither CYP2D6 genotypes nor metoprolol pharmacokinetics differed between patients with and those without a decompensation event. There was no association between the beta(2)-adrenergic receptor or G(s)alpha polymorphisms with decompensated heart failure. Patients with the Gly389 variant and Ser49Ser genotype were significantly more likely to require increases in heart failure medications during beta-blocker titration and thus may require more frequent follow-up during titration.

Modulation of Metoprolol Pharmacokinetics and Hemodynamics by Diphenhydramine Coadministration during Exercise Testing in Healthy Premenopausal Women

Premenopausal women may be most vulnerable to acute coronary syndromes at a point in their menstrual cycle when their plasma estrogen levels are the lowest during and immediately after menstruation. Metoprolol is a first-line drug in the management of patients with acute coronary syndrome; however, when metoprolol was marketed in 1982, women were largely excluded from clinical trials. Furthermore, the over-the-counter antihistamine diphenhydramine inhibited the metabolism of the CYP2D6 substrate metoprolol in healthy, young men with pharmacokinetic and pharmacodynamic consequences. The pharmacokinetics and pharmacodynamics of metoprolol and its interaction with diphenhydramine were investigated in a randomized, double-blind, crossover, placebo-controlled manner in healthy, premenopausal extensive (EM; n = 16) and poor metabolizer (PM; n = 4) women immediately after menstruation. During the placebo phase, EMs had between 5.2- and 8.4-fold higher total clearance (CL/F) of R- and S-metoprolol compared with PMs, whereas the latter had a 35% greater area under the effect curve (AUEC) and 60% greater EC(50) value for heart rate reduction than EMs (all P < 0.05). Diphenhydramine coadmininstration caused a 2.2- to 3.2-fold decrease in CL/F of metoprolol enantiomers with a resulting 21% increase in AUEC and 29% increase in EC(50) value for heart rate reduction in EMs (all P < 0.05). This is the first study to report an in-depth elucidation of metoprolol's pharmacokinetics and hemodynamics in premenopausal EM and PM women at a point in their menstrual cycle when vulnerability for acute coronary events may be greatest. Caution is warranted when the over-the-counter antihistamine diphenhydramine is part of a chronic therapeutic regimen.

Pharmacokinetic Drug Interactions of Gefitinib with Rifampicin, Itraconazole and Metoprolol

Gefitinib (IRESSA, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, has been approved in several countries for the treatment of advanced non-small-cell lung cancer. Preclinical studies were conducted to determine the cytochrome P450 (CYP) isoenzymes involved in the metabolism of gefitinib and to evaluate the potential of gefitinib to cause drug interactions through inhibition of CYP isoenzymes. Based on these findings, three clinical studies were carried out to investigate pharmacokinetic drug interactions in vivo with gefitinib. In preclinical studies radiolabelled gefitinib was incubated with: (i) hepatic microsomal protein in the presence of selective CYP inhibitors; and (ii) expressed CYP enzymes. Human hepatic microsomal protein was incubated with selective CYP substrates in the presence of gefitinib. Clinical studies were all phase I, open-label, single-centre studies; two had a randomised, two-way crossover design and the third was nonrandomised. The first and second studies investigated the pharmacokinetics of gefitinib in the presence of a potent CYP3A4 inducer (rifampicin [rifampin]) or inhibitor (itraconazole) in healthy male volunteers. The third study investigated the effects that gefitinib had on the pharmacokinetics of metoprolol, a CYP2D6 substrate, in patients with solid tumours. The results of preclinical studies demonstrated that CYP3A4 is involved in the metabolism of gefitinib and that gefitinib is a weak inhibitor of CYP2D6 activity. In clinical studies when gefitinib was administered in the presence of rifampicin, geometric mean (gmean) maximum concentration and area under the plasma concentration-time curve (AUC) were reduced by 65% and 83%, respectively; these changes were statistically significant. When gefitinib was administered in the presence of itraconazole, gmean AUC increased by 78% and 61% at gefitinib doses of 250 and 500 mg, respectively; these changes also being statistically significant. Coadministration of metoprolol with gefitinib resulted in a 35% increase in the metoprolol area under plasma concentration-time curve from time zero to the time of the last quantifiable concentration; this change was not statistically significant. There was no apparent change in the safety profile of gefitinib as a result of coadministration with other agents. Although CYP3A4 inducers may reduce exposure to gefitinib, further work is required to define any resultant effect on the efficacy of gefitinib. Exposure to gefitinib is increased by coadministration with CYP3A4 inhibitors, but since gefitinib is known to have a good tolerability profile, a dosage reduction is not recommended. Gefitinib is unlikely to exert a clinically relevant effect on the pharmacokinetics of drugs that are dependent on CYP2D6-mediated metabolism for their clearance, but the potential to increase plasma concentrations should be considered if gefitinib is coadministered with CYP2D6 substrates that have a narrow therapeutic index or are individually dose titrated.

Pharmacokinetics and genotypes do not predict metoprolol adverse events or efficacy in hypertension

Beta-Blocker use can be associated with adverse effects that may have an impact on adherence or harm patients. The commonly prescribed beta-blocker metoprolol is metabolized by the polymorphic cytochrome P450 (CYP) 2D6 enzyme, resulting in widely variable drug exposure. We investigated whether metoprolol plasma concentrations, CYP2D6 polymorphisms, or genotype-derived phenotype was associated with adverse effects or efficacy in patients with hypertension. Fifty hypertensive patients received metoprolol by use of a dose-titration algorithm until target blood pressure was reached, intolerable side effects occurred, or maximal daily dose was achieved. CYP2D6 genotype was determined by methods based on polymerase chain reaction-restriction fragment length polymorphism and included 19 allelic variants. Patients were assigned to standard phenotype groups on the basis of genotype. Patients were also assigned activity scores based on functional activity of the alleles. General and dose-limiting adverse events and blood pressure responses were analyzed in relation to metoprolol steady-state pharmacokinetic profile and CYP2D6 genotype-derived phenotype. Poor metabolizers had a significantly longer elimination half-life, higher S-metoprolol area under the plasma concentration-time curve (AUC), and lower oral clearance (P < or = .007 for all parameters). There was a 29.6-fold variability in AUC among extensive metabolizers, which was largely explained by CYP2D6 activity scores (P = .032 for ordered differences in AUC by activity score among extensive metabolizers). Overall general and dose-limiting adverse event rates were 46% and 14%, respectively. General adverse event rates did not differ by AUC quartile (66.7% [95% confidence interval (CI), 35.4%-88.7%] and 41.7% [95% CI, 16.5%-71.4%] in the lowest and highest quartiles, respectively; P = .09 among all quartiles). Dose-limiting adverse event rates were also not different by AUC quartile (16.7% [95% CI, 2.9%-49.1%] and 8.3% [95% CI, 0.4%-40.2%] in the lowest and highest quartiles; P = .35 among all quartiles). Furthermore, adverse event rates did not differ by activity scores or between extensive, intermediate, or poor metabolizers. Antihypertensive response rate and blood pressure changes also were not influenced by differences in plasma concentrations or CYP2D6 genotypes. As expected, CYP2D6 genotype-phenotype correlates with differences in metoprolol pharmacokinetics. However, there was no association between variable pharmacokinetics or CYP2D6 genotype and beta-blocker-induced adverse effects or efficacy.